The peripheral nervous system may be subjected to multiple simultaneous insults. These include trauma, inflammation, the effects of diseases such as diabetes and drugs, or toxins. Interactions are difficult to study in vivo. In this proposal, we will use modified isobolographic analysis to study the interaction between hypoxia- and suramin-induced neurotoxicity. One of the proposed mechanisms underlying diabetic neuropathy is vascular pathology resulting in neural hypoxia or ischemia. Suramin is an experimental chemotherapeutic agent used in the treatment of solid tumors including breast and prostate cancers. One of the dose-limiting side effects of this agent is peripheral neuropathy. The mechanisms of hypoxia- and antineoplastic agent-induced nerve injury in the peripheral nervous system (PNS) have not been fully defined and the effect of double insults has been difficult to study. We propose that suramin and hypoxia both produce nerve injury by way of calcium-mediated pathways. Using primary dorsal root ganglion neurons as an in vitro model system, we will study the mechanism of interaction and determine whether it is synergistic or additive. If there is interaction we will test the hypothesis that convergence occurs at the level of calcium signaling.